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<p>Amiodarone hydrochloride (AMH) is a potent anti-arrhythmic drug used for the treatment of ventricular tachycardia and ventricular fibrillation, but its clinical utility is limited by low aqueous solubility (~ 0.2&#xa0;mg/mL) and poor dissolution. Co-crystallisation offers a promising strategy to improve the solubility and bioavailability of Biopharmaceutics Classification System Class II drugs. This study focused on developing an immediate-release tablet containing AMH co-crystals with enhanced solubility and dissolution characteristics. Co-former selection was guided by excess enthalpy and Hansen solubility parameter calculations, leading to the synthesis of two co-crystals, amiodarone–tartaric acid and amiodarone–phthalic acid, via liquid-assisted grinding. Characterisation was performed using powder X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy and scanning electron microscopy. The amiodarone–tartaric acid co-crystal exhibited superior solubility (0.891&#xa0;mg/mL and 0.583&#xa0;mg/mL in acetate buffer and water, respectively) compared with the pure drug. Polymer screening identified polyethylene glycol 4000 as optimal for controlling solution-mediated phase transformation. The tablet formulation, optimised using a Design of Experiments approach, achieved more than 90% drug release in 20&#xa0;min compared with 95% in 120&#xa0;min for a marketed product. Stability studies confirmed retention of crystallinity, solubility, and assay after six months, demonstrating the formulation’s robustness and potential clinical applicability.</p> Graphical Abstract <p></p>

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Rational Design of Amiodarone Co-crystals: A Synergistic Strategy Combining Computational Prediction, Precipitation-Inhibiting Polymers, and Formulation Optimisation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月4日

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  • Rahul Jha,
  • Smit Patel,
  • Arzoo Sekhani,
  • Heena A. Parmar,
  • Nimeet Desai,
  • Pranav Shah

摘要

Amiodarone hydrochloride (AMH) is a potent anti-arrhythmic drug used for the treatment of ventricular tachycardia and ventricular fibrillation, but its clinical utility is limited by low aqueous solubility (~ 0.2 mg/mL) and poor dissolution. Co-crystallisation offers a promising strategy to improve the solubility and bioavailability of Biopharmaceutics Classification System Class II drugs. This study focused on developing an immediate-release tablet containing AMH co-crystals with enhanced solubility and dissolution characteristics. Co-former selection was guided by excess enthalpy and Hansen solubility parameter calculations, leading to the synthesis of two co-crystals, amiodarone–tartaric acid and amiodarone–phthalic acid, via liquid-assisted grinding. Characterisation was performed using powder X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy and scanning electron microscopy. The amiodarone–tartaric acid co-crystal exhibited superior solubility (0.891 mg/mL and 0.583 mg/mL in acetate buffer and water, respectively) compared with the pure drug. Polymer screening identified polyethylene glycol 4000 as optimal for controlling solution-mediated phase transformation. The tablet formulation, optimised using a Design of Experiments approach, achieved more than 90% drug release in 20 min compared with 95% in 120 min for a marketed product. Stability studies confirmed retention of crystallinity, solubility, and assay after six months, demonstrating the formulation’s robustness and potential clinical applicability.

Graphical Abstract